Role of Znf750 in skin development

The skin epidermis is a constantly renewing stratified epithelial tissue that provides essential protective barrier functions. The major barrier is at the outermost layers of the epidermis, formed by terminally differentiated keratinocytes reinforced by proteins and lipids of their cornified envelope (CE), and disruptions to this process characterizes common skin disorders. ZNF750 is an epithelial transcription factor essential for in vitro keratinocyte differentiation, whose autosomal dominant mutation in humans causes psoriasis-like skin disease. Here, we report epidermal-specific Znf750 conditional knockout mouse model utilized to uncover the role of Znf750 in epidermal development. We show that deletion of Znf750 in the developing skin does not block epidermal differentiation, suggesting in vivo compensatory feedback mechanisms, yet results in impaired barrier function and perinatal lethality. Molecular dissection uncovered ultrastructural defects in the differentiated layers of the epidermis, accompanied by alterations in the expression of ZNF750-dependent genes encoding for key proteins and lipids involved in CE formation, including gene subsets known to be mutated in skin disease with impaired barrier function. Newborn mouse epidermal cells were purified fromZnf750 knock out and control mice, and RNA was analyzed by RNA-seq.皮肤表皮（skin epidermis）是一类持续自我更新的复层上皮组织，承担着不可或缺的保护性屏障功能。其核心屏障结构位于表皮最外层，由终末分化的角质形成细胞（keratinocytes）构成，这类细胞通过自身分泌的蛋白质与脂质所构建的角化包膜（cornified envelope, CE）得到强化；该屏障形成过程的紊乱，是诸多常见皮肤疾病的典型特征。ZNF750是一种上皮特异性转录因子，对体外培养的角质形成细胞分化过程至关重要，人类体内该基因的常染色体显性突变可引发银屑病样皮肤疾病。本研究构建了表皮特异性Znf750条件性敲除（conditional knockout）小鼠模型，用于探究Znf750在表皮发育中的调控功能。实验结果表明，在发育中的皮肤组织中敲除Znf750并不会阻断表皮分化程序，这提示体内存在代偿性反馈调控机制，但会导致表皮屏障功能受损，并引发围产期致死现象。分子机制解析显示，表皮分化层存在超微结构缺陷，同时伴随ZNF750依赖型基因的表达谱改变：这些基因编码参与角化包膜形成的关键蛋白质与脂质，其中包括已知在屏障功能受损的皮肤疾病中发生突变的基因子集。本研究从Znf750敲除小鼠与对照小鼠体内纯化了新生小鼠表皮细胞，并通过RNA测序（RNA-seq）对其转录组进行了分析。